WO2004098592A1

WO2004098592A1 - Composition containing oxazolidinone derivative

Info

Publication number: WO2004098592A1
Application number: PCT/JP2004/006425
Authority: WO
Inventors: Kazuhisa Tsujimoto; Osamu Sakai; Yoshikuni Nakamura; Katsuhiro Inada; Kayoko Ueda
Original assignee: Senju Pharmaceutical Co. Ltd.
Priority date: 2003-05-06
Filing date: 2004-05-06
Publication date: 2004-11-18

Abstract

A stabilized composition for treatments for allergic eye diseases and ophthalmia which contains 5-(4-methoxy-3-propoxyphenyl)-5-methyl-2-oxazolidinone or a pharmacologically acceptable salt thereof. In particular, it is a composition for topical administration particularly for eyes.

Description

Technical Field of the Invention Compositions containing oxazolidinone derivatives

The present invention relates to a composition containing 5- (4-methoxy-3-propoxyphenyl) -1-methyl-21-year-old xazolidinone or a pharmaceutically acceptable salt thereof. Ming background technology

The following equation (I)

Rice field

And the chemical name is (R)-(-)-5- (4-methoxy-13-propoxyphenyl) _5-methyl-2-xoxazolidinone (generic name: mesopram) Xazolidinone derivatives are known (for example, Japanese Patent Application Laid-Open No. 7-61978, Japanese Patent Publication No. 7-42229, and Japanese Patent Application Laid-Open No. 1-513693). 5- (4-Methoxy-3-propoxyphenyl) -1-5-methyl-2-oxazolidinone is known as an anti-allergic agent having an inhibitory effect on phospho-diesterase IV (PDE-IV), atopic dermatitis It is effective against allergic diseases such as asthma and chronic obstructive pulmonary disease.

However, with respect to 5- (4-methoxy-3-propoxyphenyl) -1-5-methyl-2-oxazolidinone, it is considered to be a composition for topical ocular administration for the treatment of allergic monocular eye disease or for the treatment of ocular inflammation. It is not known whether it is useful as a composition for topical administration to the eye.

In order for topical ocular administration to be effective against allergic or inflammatory eye diseases, the drug must reach the affected area and stay there for the required time at the required concentration. Also, since it is administered topically to the eye, it is necessary that there be no eye irritation or that the eye irritation be minimal enough to withstand use.

Also, 5- (4-methoxy-3-propoxyphenyl) -1-methyl-2-year-old xazolidinone is a compound that is hardly soluble in water and unstable in water. Conventionally, it is necessary to produce poorly water-soluble drugs as aqueous solutions such as eye drops and nasal drops. In such a case, a surfactant or the like is added. In addition, Japanese Patent Publication No. Hei 5-770612 discloses non-steroidal antirheumatic drugs, steroids, cardiac glycosides, benzodiazepine derivatives, benzimidazole derivatives, piperidine derivatives, piperazine derivatives, imidazole derivatives. And a method for solubilization of a poorly soluble conjugate such as a triazole derivative using a cyclodextrin, for example, hydroxyethyl-1-i8-cyclodextrin ゃ hydroxypropyl-1; 8-cyclodextrin.

However, the solubilization of a poorly soluble drug depends on the shape, size, physical and chemical properties of the poorly soluble drug, and the physical and chemical properties of the solubilizer used. At present, it is not easy to produce a stable aqueous solution of a poorly soluble drug because the combination and the mixing ratio are different. As far as the present inventors know, 5- (4-methoxy-3-propoxyphenyl) -5-methyl-2-year-old xazolidinone is described in terms of its stable aqueous solution and its solubilization method. There is no document that describes this method or suggests such a method.

On the other hand, the pathogenesis of corneal ulcers involves the activity of inflammatory cells such as corneal stromal cells and neutrophils, and complex interactions are induced through cytokins and proteases secreted by them. It is thought to form a pathological condition. Currently, steroids are used for corneal ulcers, but there are various problems such as susceptibility to infection and increased intraocular pressure. Therefore, development of a useful and safe drug for corneal ulcer is desired. PDE-IV inhibitors are known to have an inhibitory effect on cytoplasmic in production (inflammatory cells), neutrophil migration and MMP production (HLF-1 human lung-derived fibroblasts). ing.

JP-T-2003-520825 discloses the treatment of a corneal ulcer with an α-sulfonylhydroxamic acid derivative which is a phosphodiesterase inhibitor. In addition, Japanese Patent Application Publication No. 2002-53373883 discloses that the level of cyclic adenosine monophosphate (3 ', 5'-monophosphate (cAMΡ)) is increased by inhibiting PDE-IV. A compound and a pharmaceutical composition for treating a disease are disclosed, and corneal ulcer is exemplified as one of the target diseases. However, it is known that (R)-(-)-5- (4-methoxy-13-propoxyphenyl) -1-methyl-12-year-old xazolidinone has a therapeutic effect on corneal ulcer by topical administration to the eye. Not. Disclosure of the invention

An object of the present invention is to provide a stable composition containing 5- (4-methoxy-3-propoxyphenyl) -5-methyl-2-year-old xazolidinone or a pharmaceutically acceptable salt thereof. It is in.

A further object of the present invention is to provide 5- (4-methoxy-13-propoxyphenyl) -1-methyl-2-year-old xazolidinone or a pharmaceutically acceptable salt thereof. An object of the present invention is to provide a composition for topical administration to the eye for treating allergic eye diseases, for treating eye inflammation, and for treating corneal ulcer.

A further object of the present invention is to provide a stable aqueous solution containing an effective concentration of 5- (4-methoxy-3-propoxyphenyl) -5-methyl-2-agexazolidinone or a pharmaceutically acceptable salt thereof. It is to provide a liquid agent.

A further object of the present invention is to solubilize sparingly soluble 5- (4-methoxy-13-propoxyphenyl) -5-methyl-12-year-old xazolidinone or a pharmacologically acceptable salt thereof, And to provide a method for stabilization.

As a result of further studies, the present inventors have found that (R)-(-)-5- (4-methoxy-3-propoxyphenyl) -15-methyl-2-year-old xazolidinone is present in an aqueous solution, It was found that the amount of S-isomer increased with time and tended to gradually shift to the racemic form. 5- (4-methoxy-13-propoxyphenyl) -1-5-methyl-2-year-old In the case of aqueous solutions prepared using racemic as xazolidinone, this point is of course not a problem at all. In the case of a composition prepared using the (R) form, there is room for improvement by further stabilization. Accordingly, a further object of the present invention is to provide (R)-(-)-5- (4-methoxy-13-propoxyphenyl) -5-methyl-12-year-old xazolidinone or a pharmaceutically acceptable salt thereof. It is an object of the present invention to provide a composition for topical administration, which contains the compound in a form where its racemization is prevented.

A still further object of the present invention is to provide a poorly soluble (R)-(-)-5- (4—methoxy-13-propoxyphenyl) -1-methyl-12-year-old xazolidinone or An object of the present invention is to provide a method for preventing racemization of a pharmacologically acceptable salt.

Accordingly, the present invention provides the following. -1.5-(4-Methoxy-3-propoxyphenyl)-5-Methyl-

(2) A composition for topical ocular administration for treating allergic eye diseases, comprising one-year-old xazolidinone or a pharmaceutically acceptable salt thereof.

2. A composition for topical administration to the eye for the treatment of ocular inflammation, comprising 5- (4-methoxy-3-propoxyphenyl) -5-methyl-2-oxazolidinone or a pharmaceutically acceptable salt thereof.

3.5- (4-Methoxy-1-propoxyphenyl) Composition for topical administration to the eye for treatment of corneal ulcer, comprising 15-methyl-12-oxazolidinone or a pharmacologically acceptable salt thereof. object.

4. (R)-(-)-5- (4-Methoxy-3-propoxyphenyl) -5-methyl-2-year-old oxazolidinone or a pharmacologically acceptable salt thereof. A composition for topical administration to the eye for treating diseases.

5. (R)-(-)-5- (4-Methoxy-3-3-propoxyphenyl) (1) A composition for topical administration to the eye for treating ocular inflammation, which comprises 5-methyl-2-year-old xazolidinone or a pharmaceutically acceptable salt thereof.

6. (R) I (-) I 5-(4-Methoxy-3-propoxyphenyl) -5-methyl-2-year-old containing oxazolidinone or a pharmaceutically acceptable salt thereof for treating corneal ulcer A composition for topical administration to the eye.

7. The composition for topical ocular administration according to any one of the above 1 to 6, which is in the form of an aqueous solution.

8. The composition for topical ocular administration according to any one of the above 1 to 6, which is in the form of a suspension.

9. The composition for ocular topical administration according to any one of the above 1 to 6, which is in the form of an oily ophthalmic solution.

10. The composition for topical administration to the eye according to any one of the above 1 to 6, which is in the form of an emulsion.

1 1. (R)-(-) — 5— (4-Methoxy-13-propoxyphenisole) -1-Methyl-2-year-old xazolidinone and its pharmacologically acceptable salts 0.001 wZv% and upper limit concentration 2. The composition for topical ocular administration according to any one of the above items 1 to 10, which is in the range defined by OwZv ^.

1 2. The composition for topical ocular administration according to any one of the above 1 to 6, which is in the form of an ointment.

1 3. (R) 1 (1) 1 5- (4-Methoxy-13-propoxyphenyl) 1-5-Methyl-2-year-old xazolidinone and its pharmacologically acceptable salt concentration are lower than the lower limit. The composition for topical administration to the eye according to any one of 1 to 6 and 12 above, which is in the range defined by 0.001 wZw% and the upper limit concentration of 10. OwZw%.

14.5- (4-Methoxy-3-propoxyphenyl) 1-methyl-2-agexazolidinone or a pharmacologically acceptable salt thereof and hydroxypropyl-containing aqueous solution containing 8-cyclodextrin .

1 5. Hydroxypropyl 1) 8-cyclodextrin The lower limit of the concentration is 0.5 wZv% and the upper limit is selected from the range of 25 wZv%.

4. The aqueous liquid preparation according to 4.

16.5- (4-Methoxy-3-propoxyphenyl) 1-5-methyl 12-year-old xazolidinone and its pharmacologically acceptable salt concentration is lower than 0.001 w / V% 16. The aqueous liquid preparation according to the above 14 or 15, wherein the aqueous liquid preparation is in a range specified by 2.0 w / v%.

17. The aqueous liquid preparation according to any one of the above items 14 to 16, wherein the pH of the aqueous liquid preparation is in the range of 3 to 9. 1 8. The aqueous liquid preparation according to any one of the above items 14 to 17, which is an ophthalmic solution.

1 9. The aqueous liquid preparation according to any one of the above items 14 to 17, which is a nasal drop. 20. The aqueous liquid preparation according to any one of the above items 14 to 17, which is an eardrop.

2 Ί. (R)-(I) 1 5-(4-Methoxy 3-Propoxyphenyl) 1 5-Methyl 2-year-old xazolidinone or its pharmacologically acceptable salt 0.0 1 wZv% ~ Aqueous ophthalmic solution containing 0.1 w_V% and hydroxypropyl mono-S-cyclodextrin 3.0 · w / v% to 12.5 V%.

22.5- (4-Methoxy-3-propoxyphenyl) -15-methinole-12-oxazolidinone or a pharmaceutically acceptable salt thereof with hydroxypropyl-1-i8-cyclodextrin A method for solubilizing and stabilizing 5- (4-methoxy-13-propoxyphenyl) -1-methyl-2-oxazolidinone and a pharmaceutically acceptable salt thereof in an aqueous solution.

23. (R)-(-)-15- (4-methoxy-3-propoxyphenyl) -15-methyl-2-oxazolidinone or its pharmacologically acceptable salt contained in an oily liquid base An oily liquid composition for topical administration, wherein the base comprises castor oil and triglyceride or a medium-chain fatty acid.

24. The concentration of (R)-(-)-5- (4-methoxy-13-propoxyphenyl) -1-methyl-2-oxazolidinone and its pharmacologically acceptable salts is reduced to a lower limit of 0. 001 w / v% and upper limit concentration 2. The oily liquid composition for topical administration according to the above item 23, which is in the range specified by Ow / v%.

25. The oily liquid composition for topical administration according to the above item 23 or 24, which is an ophthalmic solution.

26. The oily liquid composition for topical administration according to the above item 23 or 24, which is a nasal solution.

27. The oily liquid composition for topical administration according to the above item 23 or 24, which is an eardrop.

28. Racemization of (R)-(1-)-1- (4-methoxy-3-propoxyphenyl) -1-5-methyl-2-year-old xazolidinone and Z or a pharmacologically acceptable salt thereof in a liquid preparation (R)-(-)-5- (4-methoxy-13-propoxyphenyl) -1-methyl-2-oxazolidinone and Z or a pharmacologically acceptable salt thereof. A method comprising blending an oil and / or a medium-chain fatty acid triglyceride into an oily liquid preparation.

According to the present invention, a stabilized composition for treating allergic diseases and inflammatory diseases such as allergic eye disease treatment, inflammatory eye disease treatment and corneal ulcer treatment can be obtained. The composition can be used in various applications including injections, and is particularly suitable for use as a composition for topical administration to the eye and other compositions for topical administration. Therefore, the composition for topical administration to the eye of the present invention can be used as an aqueous solution such as ophthalmic solution, suspension ophthalmic solution, emulsion or the like, an oily solution or an ointment, allergic conjunctivitis, allergic eye diseases such as spring catarrh, grape It is advantageously used for the treatment of ocular inflammation such as meningitis, blepharitis, lacrimal canalitis, oculophthalmitis, and postoperative endophthalmitis. The composition for topical administration to the eye of the present invention is also useful as a therapeutic agent for corneal ulcer. Further, the aqueous solution and the composition for topical administration of the present invention are advantageously used for allergic diseases such as atopic dermatitis, asthma and chronic obstructive pulmonary disease. Brief description of the drawings

FIG. 1 is a graph showing the inhibitory effects of the suspension of the present application, rolipram and full-year rometron on the LTD ₄ and PAF-induced conjunctival eosinophil models in Experimental Example 1. The vertical axis represents the absorbance (490 nm). RP indicates rolipram. FM indicates full-length Rometron. Each column shows the average soil standard error. In the figure, ** indicates a significant difference (P <0.01) from the control (Dumiett's test). Each group other than the normal group has n = 4 to 5, and the normal group has n = 2.

FIG. 2 is a diagram showing the inhibitory effects of the suspension of the present application, betamethosone and full-year rometron on antigen-induced conjunctivitis in Experimental Example 1. The vertical axis represents the score or absorbance (490 nm). BM indicates a solid evening zone. FM indicates full-length rometron. Each column shows the average soil standard error. In the figure, ** indicates a significant difference (P <0.01) from the control (Dunnett's test). π = 7-8.

FIG. 3 is a diagram showing the inhibitory effects of the aqueous solution of the present application and betamethasone on antigen-induced conjunctivitis in Experimental Example 1. The vertical axis represents the score or absorbance (490 nm). BM indicates solid zoning. Each column shows the mean standard error. In the figure, ** indicates a significant difference (P 0.01) from the control (Dunnett's test). n = 9-10.

Figure 4 is a graph showing the effect of (R)-(-)-15- (4-methoxy-3-propoxyphenyl) -15-methyl-2-year-old xazolidinone on endotoxin-induced corneal opacity by eye drops. is there.

FIG. 5 is a graph showing the effect of (R)-(—)-15- (4-methoxy-13-propoxyphenyl) -15-methyl-2-year-old xazolidinone on endotoxin-induced corneal neovascularization. It is. BEST MODE FOR CARRYING OUT THE INVENTION

The compounds of the present invention contained in the composition for topical administration to the eye of the present invention include racemic forms, (R) forms and (S) forms. Of these, the racemic form, the (R) form, and a mixture of the (R) form and the (S) form, which are located between the two and contain the (R) form in a ratio of 1 Z2 or more, are preferable. Particularly preferred. 5-(4-Methoxy-3-propoxyphenyl)-5-methyl-2-year-old oxazolidinone is a pharmacologically acceptable salt of sodium salt such as sodium salt and potassium salt. Metal salts may be mentioned, but any other salts may be used as appropriate for the purpose of the present invention, as long as they are pharmacologically acceptable salts.

5- (4-Methoxy-3-propoxyphenyl) 15-methyl-12-oxazolidinone is described in, for example, the above-mentioned Japanese Patent Application Laid-Open No. Hei 7-6-1978 and Japanese Patent Laid-Open Publication No. Hei 11-113. It can be produced by the method described in JP-A-693.

When the composition for topical administration to the eye of the present invention is in the form of an aqueous solution such as an ophthalmic solution, a suspended ophthalmic solution or an emulsion, for example, (R)-(1-)-5- (4-methoxy-13-) Propoxyphenyl)-5-Methyl-12-year-old xazolidinone or its pharmacologically acceptable salt content usually has a lower limit of about 0.001 w / v%, preferably about 0.005 w / v%. , More preferably about 0.01 w / v%, upper limit 2.about Ow / v%, preferably about 0.5 w / v%, more preferably about 0.1 w / v%, It may be increased or decreased as appropriate according to the purpose and the degree of the indication.

Further, in the aqueous liquid preparation of the present invention, the content of hydroxypropyl 1 / 5-cyclodextrin is lower limit of about 0.5 w / v%, preferably about 3. Ow / v%, more preferably 5. Ow / v%. %, The upper limit is about 25 w / v%, preferably about 12.5 w / v%, more preferably about 8. Ow / v%, and the particularly preferable content is about 6.5 w / v%.

When the composition for topical administration to the eye of the present invention is in the form of an ophthalmic ointment, for example, (R) 1 (-)-5- (4-methoxy-3-propoxyphenyl) 15-methyl-1-2 —The content of oxazolidinone or a pharmacologically acceptable salt thereof is generally lower limit of about 0.001 w / w%, preferably about 0.005 w / w%, more preferably about 0.01 w / w%. / w%, upper limit: 10 Ow / w%, preferably about 2.0 w / w%, more preferably about 0.1 w / w%, depending on the intended use and the degree of indication May be appropriately increased or decreased.

When the composition for topical administration to the eye of the present invention is in the form of an aqueous solution such as an ophthalmic solution, a suspension ophthalmic solution or an emulsion, it does not contradict the purpose of the present invention. Various additives such as a buffer, a thickening agent, a chelating agent, a preservative, a pH adjuster, and a fragrance may be appropriately added.

Examples of the tonicity agent include sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, glucose, propylene glycol and the like. Examples of the buffer include phosphate buffer, borate buffer, citrate buffer, tartrate buffer, acetate buffer, sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium citrate, boric acid , Sodium borate, sodium acetate, amino acids and the like. Polyvinyl pyrrolidone, cal Examples include boxymethylcellulose, carboxypropylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, and sodium polyacrylate. Examples of the chelating agent include sodium edetate, sodium citrate, and condensed sodium phosphate. Examples of preservatives include quaternary ammonium salts such as benzalkonium chloride and benzonium chloride, para-hydroxybenzoic esters such as methyl paraoxybenzoate and propyl parahydroxybenzoate, chlorhexidine dalconate, Sorbic acid and its salts, thimerosal and the like. Examples of the pH adjuster include hydrochloric acid, sodium hydroxide, phosphoric acid, and acetic acid. Examples of the fragrance include 1-men I-one, borneol, camphor, and eucalyptus oil.

The concentration of each of the above-mentioned additives blended in the composition for topical administration to the eye of the present invention is, for example, the isotonic agent is blended to a concentration such that the osmotic pressure ratio becomes about 0.8 to 1.2, and the buffer is 0.8. The content of the thickener is about 0.1 to 1 OwZv%.

The composition of the present invention comprises (R)-(-)-5- (4-methoxy-3-propoxyphenyl) -1-methyl-2-year-old xazolidinone or a pharmaceutically acceptable salt or oil thereof. Liquid (oil-based liquid) using an oil as a medium (for example, a solution in which the present compound is dissolved or suspended in an oil as a base), alcohol such as ethanol, water, and It may be an oil-based liquid (oil-based liquid) further containing an emulsifier. As the types of oils that can be used in the present invention, those that can be applied to eyes with low toxicity and low irritation are used. Examples of oils include those containing fatty acid esters of glycerin, such as soybean oil, sesame oil, camellia oil, rapeseed oil, corn oil, etc., and particularly suitable are castor oil and medium-chain fatty acid esters. Liglycerides [for example, Miglyol (trade name, Mitsuba trade)] can be mentioned.

When the castor oil and the medium-chain fatty acid triglyceride are used in combination in the composition of the present invention, the quantitative ratio between the two may be arbitrary. In addition, when an alcohol that is miscible with oil is added, the amount thereof may be appropriately determined. When water and an emulsifier are contained, those components can be added in appropriate amounts as long as the medium is maintained as an oil. The same applies when other oils are used.

When the composition for topical administration to the eye of the present invention is in the form of an oily solution, for example, (R)-(-)-5- (4-methoxy-3-propoxyphenyl) 15-methyl-2 1-year-old xazolidinone Or, the content of the pharmacologically acceptable salt thereof is usually lower limit of about 0.001 w / v%, preferably about 0.005 w / v%, more preferably about 0.01 w / v%, Upper limit: about 2.0 w / v%, preferably about 0.5 w / v%, more preferably about 0.25 w / v%, still more preferably 0.1 w / v% The dose may be adjusted according to the purpose of use and the severity of the indication. The composition of the present invention can also be provided as an aqueous preparation such as an oil-in-water (OZW) emulsion or microemulsion.

In the present invention, a surfactant, for example, a nonionic surfactant having a surface activity can be blended as an emulsifier. Examples of nonionic surfactants include polyoxyethylene hydrogenated castor oil or polyoxyethylene sorbitan fatty acid ester, preferably polyoxyethylene sorbitan monolate and polyoxyethylene sorbitan monolaurate. Polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, and the like.

When the composition for topical administration to the eye of the present invention is used in the form of an aqueous solution as an ophthalmic solution, a suspension ophthalmic solution or an emulsion, the pH is adjusted to about 3 to 9, preferably about 6 to 8. .

When the composition for topical administration to the eye of the present invention is used as an ophthalmic ointment, purified lanolin, vaseline, plastibase, liquid paraffin and the like are appropriately used as the ointment base.

The composition for topical administration to the eye of the present invention may appropriately contain other same or different kinds of pharmaceutically active ingredients as long as the object of the present invention is not adversely affected.

The composition for topical administration to the eye of the present invention can be produced by a method known per se, for example, a method described in a liquid preparation such as an eye drop in the Japanese Pharmacopoeia, the 14th Revised Japanese Pharmacopoeia, general rules for preparations, or an ointment. it can.

The composition for topical administration to the eye of the present invention can be used in warm-blooded animals (for example, humans, rats, mice, rabbits, rabbits, dogs, cats, etc.).

The composition for topical administration to the eye of the present invention is, for example, (R)-(1-)-5- (4-methoxy-13-propoxyphenyl) -5-methyl-2-year-old xazolidinone 0.1 w / v % For eye drops as an ophthalmic solution containing 1%, it is sufficient to apply 1 to 2 drops at a time, 3 to 6 times a day. The number of administrations can be increased or decreased as appropriate depending on the degree of the indication.

The composition for topical administration of the present invention is used as an ointment in the form of an ophthalmic ointment. When used for ocular inflammation, for example, the present invention contains 0.1 w / w% of (R)-(—)-5- (4-methoxy-3-propoxyphenyl) -15-methyl-2 one-year-old xazolidinone. Ophthalmic ointment may be given to adults 3 to 6 times daily. The number of administrations can be increased or decreased as appropriate depending on the degree of the adaptation symptom. Hereinafter, the present invention will be described in more detail with reference to experimental examples and examples. The light is not limited by these.

Experimental Example 1 (R) — (1) 15- (4-Methoxy-3-propoxyphenyl) 5-Methyl-2-solubilization test of xazolidinone

(1) Solubility of (R)-(-)-5- (4-methoxy-1-3-propoxyphenyl) -5-methyl-2-xoxolidinone in various pH aqueous solutions

(experimental method)

0.1% citrate buffer (pH 3.0), 0.1% acetate buffer (pH 4.0 and 5.0) and 0.1% phosphate buffer (pH 6 (0, 7.0 and 8.0) 1 Om L each with (R)-(1-)-15- (4-methoxy-13-propoxyphenyl) -5-methyl-2-oxazolidinone 4 Omg The mixture was subjected to ultrasonic treatment and stirred vigorously for 3 hours. After confirming the pH, the mixture was centrifuged (3,500 rpm, 15 minutes), and (R)-(-)-5- (4-methoxy-3-propoxyphenyl) in the supernatant was used. The 5-methyl-2-year-old xazolidinone content was determined by the HPLC method.

(Experimental result)

The results are shown in Table 1. Table 1 Solubility of (R)-(-)-15- (4-methoxy-13-propoxyphenyl) -1-5-methyl-2-oxazolidinone in various PH aqueous solutions

As is evident from Table 1, the solubility of (R)-(1-)-15- (4-methoxy-3-propoxyphenyl) -15-methyl-12-oxazolidinone at pH 3.0-8.0 Showed almost the same value at any pH, from 0.067 to 0.071%. Experimental Example 2 Solubility of (R)-(-)-1-5- (4-methoxy-3-propoxyphenyl) -5-methyl-2-oxazolidinone at pH 7.0 using various additives

(experimental method)

In 0.1% phosphate buffer (pH 7.0), using the additives shown in Table 2, (R)-(-)-5- (4-methoxy-13-propoxyphenyl) The solubility of 5-methyl-2-year-old xazolidinone was measured. (R)-(-)-5- (4-Methoxy-13-propoxyphenyl) -1 5-Methyl-2-xoxazolidinone in 1 OmL of an aqueous solution containing 0.5% of additive 0.05 0.1 g was added, and the mixture was sonicated and stirred vigorously for 3 hours. After confirming the pH, centrifuge (3500 rpm, (15 minutes), and the content of (R)-(-)-15- (4-methoxy-3-propoxyphenyl) -15-methyl-2-year-old xazolidinone in the supernatant was measured by HPLC. (Experimental result)

Table 2 shows the results. Table 2 Solubility of (R) (—)-5- (4-Methoxy-3-propoxyphenyl) —5-Methyl-2-year-old xazolidinone with various additives

As evident from Table 2, the one with the highest solubilizing power was hydroxypropyl-1; 8-cyclodextrin, and (R) -1-(-)-5- (4-methoxy-13-propoxyphenyl). ) The solubility of 1-methyl-2-oxazolidinone increased 1.6-fold when no additive was added. Experimental example 3 Study on the amount of hydroxypropyl mono-)-cyclodextrin

In 0.1% phosphate buffer (pH 7.0), add various concentrations of hydroxypropyl pill-i8-cyclodextrin, and add (R)-(1-)-5-(4- (Xy 3-propoxyphenyl) -5-methyl-2 The solubility of 21-year-old xazolidinone was measured.

As a result, the solubility of (R)-(-)-15- (4-methoxy-13-propoxyphenyl) -15-methyl-2-isoxazolidinone in proportion to the amount of added hydroxypropyl-cyclodextrin Rose. Hydroxypropyl-β- With the addition of 6.0% cyclodextrin, the solubility of (R)-(1-)-15- (4-methoxy-3--3-propoxyphenyl) -1-methyl-2-year-old xazolidinone (pH 7.0) ) Rose to 0.56%. Experimental Example 4 Stability of (R)-(1-)-15- (4-methoxy-3-propoxyphenyl) -1-5-methyl-2-oxazolidinone

(experimental method)

Prepare an aqueous solution of (R)-(-)-15- (4-methoxy-13-propoxyphenyl) —5-methyl-2-year-old xazolidinone shown in Table 3 and fill it into a 5 mL colorless glass ampoule. did. The ampoule is kept at a constant temperature and humidity of 40 ° C and 75% RH [Model LH-20-03 manufactured by Nagano Kagaku Kikai Seisakusho Co., Ltd.] and at a constant temperature of 60 ° C [Model Nagano Kagaku Kikai Seisakusho] CH20- 01M]. Four weeks later, the properties were observed with the naked eye, and the pH and the content of (R)-(1-)-15- (4-methoxy-3-propoxyphenyl) -15-methyl-2-year-old xazolidinone were measured. The content was measured by the HPLC method [however, even if the (S) form is partially formed, it cannot be distinguished from the (R) form by this method]. Table 3

(Experimental result)

The results are shown in Table 4. Table 4 0.05% (R) — (-) — 5— (4-Methoxy-3-propoxyphenyl) -1-5-methyl-2-year-old containing xazolidinone and hydroxypropyl-1-^-cyclodextrin 0.5% (R) One (one)-5-(4-Methoxy

― 3-Propoxyphenyl) 1- 5-Methyl-2- Stability of aqueous solution of xazolidinone

* 40 ° C 5 weeks Hydroxypropyl—) 8-0.05% without cyclodextrin (R) ― (1-) 15- (4-methoxy-13-propoxyphenyl) _ 5-methyl- In the case of a 2-year-old aqueous solution of xazolidinone (prescription N 0.15 to 18), the residual ratio was 7.1 to 7.9% at any pH at 60 ° C for 4 weeks. No change was observed in the properties. When stored at 40 ° C for 4 weeks, the residual ratio was 74.3 to 75.6%, and no change was observed in the properties.

6.5% hydroxypropyl mono) 8-cyclodextrin containing 0.5% (R)-(-)-5- (4-methoxy-3-propoxyphenyl) 1-methyl-1 2-year-old xazolidinone In the case of an aqueous solution (formulation No. 19 to 22), the residual ratio was 58.6 to 63.3% at any pH at storage at 60 ° C for 4 weeks, and there was no change in properties. I couldn't. When stored at 40 ° C for 4 weeks, the residual ratio was 96.1 to 98.1%, and no change was observed in the properties.

From the above, (R)-(-)-5- (4-methoxy-13-propoxyphenyl) -15-methyl-2-oxazolidinone is a compound that is hardly soluble in water and can be used in aqueous solutions at pH 5-8. Although unstable, it was solubilized by the addition of hydroxypropyl-1-cyclodextrin, and was stable as at least 5- (4-methoxy-13-propoxyphenyl) -5-methyl-21-year-old xazolidinone. It has been found that conversion can be achieved simultaneously. Experimental Example 5 0.05% and 0.25% (R)-(I)-5-(4-Methoxy-3-propoxyphenyl) -5-Methyl-2-year-old Stability of aqueous solution of xazolidinone

By varying the concentration of hydroxypropyl-i8-cyclodextrin, 0-05% and 0.25% at pH 7.0 (R)-(1)-5-(4-1-propoxy 3-propoxy) Phenyl) -5-methyl-12-year-old aqueous solution of xazolidinone was tested for stability.

(experimental method)

0.05% and 0.25% of No. 23 No. 30 shown in Table 5 (R)-(-)-5-(4-Methoxy-1- 3-propoxyphenyl)-5- An aqueous solution of methyl 1-2-year-old xazolidinone was prepared and filled in a 5 mL colorless glass ampoule. The sample is kept at a constant temperature and humidity of 40 ° C 75% RH [Model LH-20-03 manufactured by Nagano Scientific Machinery Co., Ltd.] and a constant temperature oven at 60 ° C manufactured by Nagano Scientific Machinery Model CH 20- 01M]. Four weeks later, the properties were observed with the naked eye, and the pH and (R)-(1-)-15- (4-methoxy-13-propoxyphenyl) -15-methyl-2-oxazolidinone content were measured. The content was measured by HPLC (however, even if a part of the (S) form was formed, it could not be distinguished from the (R) form). Table 5

(Experimental result)

Table 6 shows the results. Table 6 0.05% and 0.25% containing (hydroxypropyl-1) 8-cyclodextrin (R)-(-1) -1 5- (4-methoxy-3-propoxyphenyl) -1-5-methyl-21 Stability of aqueous oxazolidinone solutions

As is evident from Table 6, (R)-(-)-5- (4-methoxy-13-propoxyphenyl) -5-methyl-2-oxazolidinone was obtained at 40 ° C for 4 weeks at (R) ― (1) —5— (4-Methoxy-13-propoxyphenyl) -1-5-Methyl-2—Amount of hydroxypropyl-1-i8-cyclodextrin, almost irrespective of the concentration of xazolidinone 1. At a concentration of 5% or more, the residual amount was 90% or more. Also, as shown in the prescriptions No. 19 to 22 in Table 4 and the prescriptions N 0.26, 27, 29, and 30 in Table 6, the amount of hydroxypropyl-jS-cyclodextrin added was 5% or more. Showed a residual amount of 96% or more. Experimental Example 6 (R)-(1-)-5- (4-Methoxy-3-propoxyphenyl) -5-methyl-2-year-old stability test of xazolidinone in oil.

(experimental method)

An oily solution was prepared by dissolving the present compound in oil according to the formulation shown in Table 7 below, and the presence or absence of a change in the content of the present compound under constant temperature conditions. For Formulations 33, 34 and 35, the residual ratio of this compound (however, the (R) -form and (S) -form cannot be distinguished) was measured by HPLC, and the change in optical activity was measured to determine the optical activity. The presence of an increase in the isomer (S) -form was examined. For comparison, an aqueous solution containing hydroxypropyl mono-S-cyclodextrin (formulation No. 36) and (R)-(1-)-5- (4-methoxy) in the formulation shown in Table 8 — 3 Propoxyphenyl) 1-5-Methyl-2-year-old xazolidinone was simply dissolved in water to a concentration of 0.04% to prepare an aqueous solution (formulation No. 37). Table 7

Table 8

(Experimental result)

The test results are shown in Tables 9 and 10. Table 9 Change in the content of this compound in oil (HPLC) Formulation No.33 No.34 No.35

60 ° C

Survival rate (%) 98.9 99.4 100.1 2 weeks

80 ° C

Survival rate (%) 97.0 99.8 99.1 2 weeks Table 1 o Changes in the ratio of the optical isomer [(s) -isomer] of this compound in oily, aqueous preparations and aqueous solutions

ND: not detectable. As is clear from the above table, in the aqueous liquid formulation shown in Table 8 (formulation Mo. 36), the ratio of the optical isomer, that is, the (S) isomer increases with time, and the optical purity is reduced. Although there was a tendency to decrease, it was confirmed that each solution in which the present compound was dissolved in oil was thermally stable at all and no change between isomers occurred. This indicates that the compound of the present invention is particularly stably maintained in an oily preparation, and substantially completely stabilized even when the preparation is prepared using the (R) form (ie, not a racemic form). Is obtained. The aqueous solution (formulation No. 37) obtained by simply dissolving (R)-(-) — 5 -— (4-methoxy-13-propoxyphenyl) -1,5-methyl-2-oxazolidinone in water was used. At 40 ° C for 7 days, the ratio of the (S) form reached 42.3%. However, in the aqueous preparation containing hydroxypropyl-) 8-cyclodextrin, the (S) -form after storage at the same temperature for the same period was The ratio of the isomers is 7.6%. Hydroxypropyl-13-cyclodextrin also contains (R)-(1-)-15- (4-methoxy-3-propoxyphenyl) -15 in aqueous solution. It was found that it has an inhibitory effect on the racemization of —methyl-1-year-old xazolidinone. Experimental Example 7 Drug efficacy test

(R) 1 (1) 1 5- (4-Methoxy-3-3-propoxyphenyl) 1-5-Methyl-2 Effects of one-year-old xazolidinone on chemical mediator Yuichi and conjunctival eosinophil infiltration induced by allergy Tested.

(1) Test animals ''

300-350 g male Hartley guinea pigs purchased from SLC (Shizuoka) were used. Test animals were housed in normal animal cages under a 12 hour light / dark cycle. Food and water were available ad libitum.

(2) Test substance The test substances used in each experiment are as follows.

Test substances for LTD ₄ and PAF-induced conjunctival eosinophil wetting model

• 0.5% (R) ― (―) -5-(4-Methoxy-3-propoxyphenyl) 1-5-Methyl-2-xoxazolidinone suspension

(R) ― (1) -5- (4-Methoxy-3-propoxyphenyl) 5-methyl-2-year-old xazolidinone 0.5% was suspended in the following base (hereinafter referred to as “liquid”).

(Base)

Sodium dihydrogen phosphate dihydrate 0.1 g

Polysorbate 80 0.5 g

Sodium chloride 0.9 g

Sodium hydroxide appropriate amount

Distilled water 100 mL

pH7.0

· 1% rol ipram (Sigma)

Mouth lipram was suspended in the above vehicle at 1.0%.

■ 0.1¾ Full-year Rometron (Sai-Doma 0.1% ophthalmic solution, Senju Pharmaceutical Co., Ltd .; same hereafter)

-Saline solution

Test substance for antigen-induced allergic conjunctivitis model

(i) Comparison with steroids

■ 0.5% (R) 1 (1) 1-5 (4-Methoxy 3-propoxyphenyl) 1-Methyl 2- 2-year-old oxazolidinone suspension

• 0.1% Bethamethasone (Rinderone solution 0.1%, Shionogi & Co., Ltd .; same hereafter) · 0. Fluorometron

• saline

(i i) Comparison with Betame Yuzon

• 0.05, 0.1, 0.25% (R)-(1-) 15- (4-Methoxy-3-propoxyphenyl) -5-Methyl-2-year-old oxazolidinone solution

(R)-(I) — 5— (4-Methoxy-3-propoxyphenyl) — 5-Methyl-1-2-xazolidinone 0.05, 0.1, 0.25% was dissolved in the following base material (hereinafter referred to as “ (Referred to as an aqueous solution of the present application).

(Base)

Sodium dihydrogen phosphate dihydrate 0.1 g

Polysorbate 80 0.5 g

Hydroxypropyl mono-j8-cyclodextrin 6.5 g

Sodium chloride 0.9 g Sodium hydroxide suitable amount distilled water total amount 100 mL

pH7.0

-0.1¾ betamethasone

· Saline solution

(3) Test model

(i) Conjunctival eosinophil infiltration model with LTD ₄ and PAF

0 - 0.01% leuco Bok Lien _{_{0 4 (LTD 4) (Cayman}} ) or 0.1% Platelet activating factor (PAF) to (Sigma) 10 L was applied to the eye of guinea pigs. Six hours after application overnight, the test animals were sacrificed and the conjunctiva was immediately excised. For drug evaluation, each drug IOL was instilled 1, 0.5, 0.25 hours before application of LTD ₄ or PAF. A physiological saline solution was similarly instilled as a control group.

Eosinophil infiltration into the conjunctiva was determined as follows. 5 mL of 0.5% a-hexadecyltrimethylammonium bromide (HTAB) in 0.1 M phosphate buffered saline was added to the corneal sample. After homogenization, freezing and thawing were repeated twice, and the sample was centrifuged at 3000Xg for 10 minutes. 20 L of the supernatant was distributed to each well of a 96-well tissue culture plate. Add 40 L of EP0 substrate solution (5 mM 0-phenylenediamine dihydrochloride, 0.005% hydrogen peroxide, 50 mM Tris-HC, pH 8) to each well and stop the reaction 5 min later with 40 AtL 8N sulfuric acid Was. Absorbance was measured at 49 Onm.

(ii) Antigen-induced allergic conjunctivitis model

Guinea pig sensitization

Guinea pigs were sensitized by intraperitoneal injection of 10 Atg ovalbumin. (OA; Sigma) together with 30 mg of aluminum hydroxide. Allergic conjunctivitis was induced 14 days (first) and 15 days (second) after sensitization by instilling 10 L of 1.5% 0A. The test substance was administered by instillation at 6, 4, 1, 1 and 0.5 hours before the first and second allergic conjunctivitis induction. The control group received saline in the same manner as the drug-treated group.

A) Evaluation of early phase response (EPR)

Thirty minutes after the second sensitization, conjunctival edema was observed and evaluated at 7 levels.

0: None (negative)

1: Weak

2: Light (mild)

3: Moderate

4: Strong

5: very strong

6: The strongest

B) Evaluation of late phase response (LPR) Six hours after the second sensitization, the guinea pigs were killed and the conjunctiva was immediately excised. The conjunctiva was easily removed.

Eosinophil infiltration into the conjunctiva was assessed by measuring the activity of Eosinophi I peroxidase (EPo), a cytotoxic protein in eosinophils. That is, 1 mL of HTAB buffer (0.5% HTBA, 10 mM phosphate buffered saline (ρΗ7.4)) was added to the extracted conjunctiva, and the conjunctiva was minced with scissors. Further, 4 mL of HTAB buffer was added and stirred. The operation of freezing and thawing the minced conjunctiva in liquid nitrogen and a hot water bath at about 37 ° C is repeated twice, and centrifuged at 3, OOOrpm (LC-120, Rotor-1 TS-7, Tomy Kogyo Co., Ltd.) for 10 minutes. The supernatant thus obtained was used as a sample for measuring EP0 activity of eosinophils infiltrated into the conjunctiva.

After diluting the EP0 activity measurement sample 5-fold with HTAB buffer, this diluted measurement sample was dispensed into a 96-well plate at 20 AtL. Add 40 L of Assay buffer (5 mM o-phenylenediamine dihydrochloride), 0.005¾ hydrogen peroxide, 50 mM Tris-HCI buffer (pH 8.0) prepared just before use And left at 25 ° C for 5 minutes. The reaction was stopped by adding 40 L of 4 M sulfuric acid to the plate, and a 96-well microphone plate reader (Muiskan (registered trademark) Multisoft,

Labsystems) measured absorbance at 492 nm.

(4) Test results

(i) Conjunctival eosinophil infiltration model with LTD ₄ and PAF

As it is apparent from FIG. 1, (an indication of eosinophil infiltration) EP0 activity in the conjunctiva of the control group increased by LTD ₄ and PAF. The 0.5% suspension of the present invention significantly suppressed the increase in EP0 activity of the conjunctiva. The effect of the 0.5% suspension of the present application was higher than that of the 0.1% oral lipram and the 0.1% full-length liposome.

(ii) Antigen-induced allergic unilateral conjunctivitis model

FIG. 2 shows the results of a comparative test of the suspension of the present application with betamethasone and full-length lometron.

[0043]

A) EPR evaluation

Thirty minutes after the 0A sensitization, the conjunctival edema of the control group was measured. The 0.5% suspension of the present invention significantly suppressed conjunctival edema. The 0.1% betamethasone solution showed the same inhibitory effect as the suspension of the present application, but was not statistically significant. 0.1% Fluorometron did not significantly suppress conjunctival edema.

B) Evaluation of LPR

Six hours after the 0A sensitization, the EP0 activity of the conjunctiva was measured. The 0.5% suspension of the present invention showed an effect superior to that of 0.1% betazone and 0.1% fluorometron, and significantly suppressed the increase in EP0 activity.

Fig. 3 shows the results of a comparison test between the aqueous solution of the present application and betamethasone. 21 Japanese Patent Office] 4, _6.200

A) EPR evaluation

Conjunctival edema was suppressed by instillation of the aqueous solution of the present application. The inhibitory effects of the aqueous solutions of 0.05%, 0.1% and 0.25% of the present application were also found to be strong for 0.1% betamethasone.

B) Evaluation of LPR

The 0,05%, 0.1%, and 0.25% aqueous solutions of the present invention significantly inhibited the increase in EP0 activity in the conjunctiva, and the 0.05%, 0.1%, and 0.25% aqueous solutions of the present invention were more effective than 0.1% betamethasone. I was

Experimental example 8 Effect in a PS-induced corneal ulcer model

Test method

(1) Test drug

The test drug was 0.1% (R) — (1) -15- (4-methoxy-3-propoxyphenyl) -15-methyl-2-oxazolidinone in the following base at 0.1 wZ

It was prepared by dissolving to V%.

Base formulation

Na Η ₂ Ρ 0 ₄ ■ 2 Η ₂ 0 0.1 g

Hydroxypropyl 1-cyclodextrin 6.5 g

Sodium chloride 0.9 g

Sodium hydroxide Mm.

Appropriate amount of distilled water

100 mL

PH 7

(2) Test method

A mixture of equal volumes of 5% ketamine and 2% xylazine was administered intramuscularly (1 mIg) to the muscles of 12 birds and subjected to general anesthesia, and then 1% endotoxin derived from Pseudomonas aeruginosa dissolved in physiological saline The (lipopolysaccharide, LPS) solution was injected into the corneal stratum corneum of one eye of the egret at a rate of 0.1 i. On days 2, 4, 7, and 10 after endotoxin injection, scoring evaluation was performed on corneal opacity and corneal neovascularization according to the criteria shown in Table 11.

From the day of liposaccharide (LPS) injection to the end of the study, the test drug was administered to the endotoxin-injected eyes of six egrets four times a day at a dose of 50 〃 I each time. The base was similarly administered to the endotoxin-injected eyes of the egret.

S¾ (ri) ゥ Scoring criteria for heron keratitis

Opacity score: (degree) X (area)

Angiogenesis score: (length) X (area) (3) Test results

The results are shown in FIGS. As is clear from these figures, both corneal opacity and corneal neovascularization were significantly suppressed by administration of the test drug. This indicates that the composition of the present invention is useful for treating corneal ulcer.Example 1 Ophthalmic solution

(R) ― (-) —5— (4-Methoxy—3-propoxyphenyl) —5-Methyl—2—year-old oxazolidinone 0.1 g

Sodium dihydrogen phosphate dihydrate 0.1 g

Sodium chloride 0.6 g

Sodium hydroxide appropriate amount

Hydroxypropyl mono-jS-cyclodextrin 6.5 g

Thimerosal 0.01 g

100 mL of sterile purified water

pH7.0

The above components are used to prepare an ophthalmic solution in a conventional manner. Example 2 Ophthalmic solution (R)-(-) — 5— (4-Methoxy-1-3-propoxyphenyl) -1-5-Methyl-1-2-year-old oxazolidinone 0.01 g

Sodium glutamate 0.3 g

Sodium chloride 0.6 g

Hydrochloric acid or sodium hydroxide

Hydroxypropyl-1-cyclodextrin 6.5 g

Benzalkonium chloride 0.005 g

100 mL of sterile purified water

pH5.0

Example 3 Ophthalmic solution using the above ingredients to form an ophthalmic solution in a conventional manner

(R) ― (1-) 1 5— (4-Methoxy-1-3-propoxyphenyl) — 5-Methyl 2-oxazolidinone 0.1 g

Hydroxypropyl mono i8-cyclodextrin 6.5 g

Chlorhexidine dalconate 0.005 g

Boric acid 1.25 g

Borax suitable amount

100 mL of sterile purified water

pH7.0

The above components are used to prepare an ophthalmic solution in a conventional manner. Example 4 Ophthalmic solution

(R)-(1-)-5- (4-Methoxy-3-3-propoxyphenyl) —5-Methyl 2-2-year-old oxazolidinone 0.1 g

Hydroxypropyl) 8-cyclodextrin 6.5 g

Chlorhexidine dalconate 0.01 g

Boric acid 1.25 g

Borax suitable amount

100 mL of sterile purified water

pH7.0

The above components are used to prepare an ophthalmic solution in a conventional manner. Example 5 Suspended ophthalmic solution

(R) — (1-) 15- (4-Methoxy-1-3-propoxyphenyl) — 5-Methyl 2- 2-year-old oxazolidinone 0.5 g

Sodium dihydrogen phosphate dihydrate 0.1 g Polysorbate 80 0.5 g

Sodium chloride 0.9 g

Sodium hydroxide

Distilled water volume 100 iiiL

pH7.0

The above components are used to prepare a suspension ophthalmic solution in a conventional manner. Example 6 Eye ointment

(R) ― (I) — 5— (4-Methoxy-3-3-propoxyphenyl) 1-5-Methyl 1-2-year-old Xazolidinone 0.1 g

Liquid paraffin 1.0 g

White Pserin 100 g

An eye ointment is prepared using the above ingredients by a conventional method. Example 7 Nasal solution

(R) ― (―) — 5— (4-Methoxy-1-3-propoxyphenyl) -1-5-Methyl 2-xoxazolidinone 0.1 g

Boric acid 0.2 g

0.7 g of sodium chloride

Sodium hydroxide appropriate amount

Hydroxypropyl mono-cyclodextrin 5.0 g

Thimerosal 0.01 g

100 mL of sterile purified water

pH7.5

The above components are used to make nasal drops in a conventional manner. Example 8 Nasal solution

(R) ― (―)-5-(4-Methoxy-1-3-propoxyphenyl) -1-5-Methyl 2-oxazolidinone 0.05 g

Boric acid 1.2 g

Borax suitable amount

Hydroxypropyl 1 / 8-cyclodextrin 6.5 g

Benzalkonium chloride 0.005 g Sterile purified water Total volume 100 mL

pH7.0

The above components are used to make nasal drops in a conventional manner. Example 9 Ear drops

()-(1-) 15- (4-Methoxy-3-3-propoxyphenyl) 5-Methyl 2-oxazolidinone 0.025 g

Cuenoic acid 0.2 g

Borax suitable amount

0.8 g of sodium chloride

Hydroxypropyl i8-cyclodextrin 3.0 g

Thimerosal 0.01 g

Sterile purified water total volume 100 inL

pH7.8

The above components are used to prepare ear drops according to the usual method. Example 10 Ear Drops

(R) one (one) one five- (4-methoxy-3-propoxyphenyl) one five-methyl one two-year-old oxazolidinone 0.1 g

Sodium dihydrogen phosphate 0.2 g

Glycerin 1.6 g

Suitable amount of sodium hydroxide

Hydroxypropyl mono-j8-cyclodextrin 8.0 g

Benzalkonium chloride 0.005 g

100 mL of sterile purified water

pH7.0

The above components are used to prepare ear drops according to the usual method. Example 1 Injection

(R) one (one) one five- (4-methoxy-13-propoxyphenyl) one five-methyl 2-year-old oxazolidinone 0.05 g

Manni I ^^ 5.0 g

Suitable amount of sodium hydroxide

Hydroxypropyl-1-cyclodextrin 5.0 g

100 mL of sterile purified water

pH7.0

Using the above components, an injection solution is prepared in a conventional manner. Example 1 2 Oily ophthalmic solution

(R) 1 (1) 15- (4-Methoxy-1-3-propoxyphenyl) 1-5-Methyl-1-oxazolidinone 0.1 g Castor oil 100 mL

According to the above formula, the present compound is added to castor oil and dissolved with stirring. If necessary, dissolve by heating and sterilize by filtration to produce eye drops. Example 13 Oily eye drops

(R) 1 (1) 1 5— (4-Methoxy 3-propoxyphenyl) 1—5-methyl 2 1-year-old xazolidinone 0.1 g

Miglyol 8 1 2 N (medium chain fatty acid triglyceride) 100 mL

According to the above formula, add this compound to Miglyol 812N and dissolve it with stirring. Heat if necessary to dissolve. Example 14 Oily eye drops

(R) one (one) one 5— (4-methoxy-3-propoxyphenyl) -5-methyl 2-year-old oxazolidinone 0.1 g

Castor oil qs

Miglyol 8 1 2 N (medium chain fatty acid triglyceride) 50 mL

100 mL total volume

According to the above formula, Miglyol 812N and castor oil are mixed, and this compound is added to this solution and dissolved with stirring. Heat if necessary to dissolve. After that, make up with castor oil and sterilize by filtration to produce eye drops. Example 15 Oily eye drops

(R) one (one) — 5— (4-methoxy-3-propoxyphenyl) one 5-methyl-2-isoxazolidinone 0.01

Sesame oil 100 mL

According to the above formula, the present compound is added to sesame oil and dissolved with stirring. If necessary, dissolve by heating and sterilize by filtration to produce eye drops. Example 16 Oily eye drops

(R) 1 (1)-5-(4-Methoxy 1 3-propoxyphenyl) 1-Methyl 2-Ixazolidinone 0.05 g

Castor oil qs

Ethanol 8 mL

100 mL total volume

Mix castor oil and ethanol according to the above formula, add this compound to this solution, and dissolve with stirring. Heat if necessary to dissolve. Then, make up with castor oil and sterilize by filtration to produce eye drops. 6425

27

Example 17 Oily eye drops

(R)-(I) 1 5— (4-Methoxy-13-propoxyphenyl) — 5-Methyl 2- 2-year-old oxazolidinone 0.05 g

Miglioyl 8 1 2 N (medium chain fatty acid triglyceride)

Ethanol 8 mL

100 mL total volume

Miglyol 812N and ethanol are mixed according to the above formula, and this compound is added to this solution and dissolved with stirring. Heat if necessary to dissolve. Then, make up with Miglyol 81211 and sterilize by filtration to produce eye drops. Example 18 Oily eye drops

(R) ― (one) one 5— (4-methoxy-3-propoxyphenyl) one 5-methyl 2-xazolidinone 0.05 g

Castor oil

Miglyol 8 1 2 N (medium chain fatty acid triglyceride) 46 mL

Ethanol 8 m

100 mL total volume

Mix castor oil, Miglyol 812N and ethanol according to the above formula, add this compound to this solution, and dissolve with stirring. Heat if necessary to dissolve. Then, make up with castor oil and sterilize by filtration to produce eye drops. Example 19 Emulsion ophthalmic solution

(R) ― (-) — 5— (4-Methoxy-3-propoxyphenyl) — 5-Methyl-12-year-old oxazolidinone 0.05 g

Castor oil 5.0 g

2.2 g concentrated glycerin

Polysorbate 8 0 4.0 g

Hydrochloric acid

Sodium hydroxide appropriate amount

Purified water qs

100 mL total volume

pH 7.0

According to the above formula, concentrated glycerin and polysorbate 80 are added to purified water and dissolved with stirring with a homomixer. Then, the present compound dissolved in castor oil is added dropwise and emulsified with a homomixer. After micronization with a microfluidizer, adjust the pH, remove the solution, sterilize by filtration to produce eye drops. Example 20 Emulsion ophthalmic solution

(R)-(-) — 5— (4-Methoxy-1-3-propoxyphenyl) -1-5-Methyl 2-oxazolidinone 0.025 g Castor oil 2.5 g

Concentrated glycerin 1.1 g

Polysorbate 80 2.0 g

Hydroxypropyl 1 / 3-cyclodextrin 3.25 g

Hydrochloric acid

Suitable amount of sodium hydroxide

Purified water qs

100 mL total volume

pH 7.0

According to the above formulation, concentrated glycerin and polysorbate 80 are added to purified water, dissolved with stirring with a wood mixer, the compound dissolved in castor oil is added dropwise, and emulsified with a homomixer. Micronization is performed with a microfluidizer. Hydroxypropyl 1) 8-cyclodextrin is dissolved in purified water, and this solution and an equal amount of the above emulsified solution are stirred at 10 ° C for 1 hour, adjusted to pH, and sterilized by filtration to produce eye drops. . Example 21 Emulsion ophthalmic solution

(R) ― (―) one 5— (4-methoxy-3-propoxyphenyl) — 5-methyl — 2-year-old oxazolidinone 0.01 g

Castor oil 5.0 g

2.2 g concentrated glycerin

Polysorbate 80 4.0 g

Sodium chloride 9.O g

Hydrochloric acid

Sodium hydroxide appropriate amount

Purified water qs

100 mL total volume

pH 7.0

According to the above formula, concentrated glycerin and polysorbate 80 are added to purified water and dissolved with stirring with a homomixer. Then, the present compound dissolved in castor oil is added dropwise and emulsified with a homomixer. Immediately after emulsification, dissolve sodium chloride and micronize with a microfluidizer. Then adjust the pH and sterilize by filtration to produce eye drops. Example 22 Emulsion ophthalmic solution (R)-(-) — 5— (4-Methoxy-1-propoxyphenyl) —5-Methyl 2- 2-year-old oxazolidinone 0.01 g

Castor oil 5.0 g

2.2 g concentrated glycerin

Tyloxapol 4.0 g

Sodium chloride 9.0 g

Hydrochloric acid is star

Sodium hydroxide appropriate amount

Purified water qs

100 mL total volume

P H 7.0

In accordance with the above formula, concentrated glycerin and tyloxapol are added to purified water and dissolved with stirring in a homomixer. Then, the present compound dissolved in castor oil is added dropwise and emulsified in the homomixer. Immediately after emulsification, dissolve sodium chloride and micronize with a microfluidizer. Then adjust the pH and sterilize by filtration to produce eye drops. Example 23 Emulsion ophthalmic solution

(R)-(1-) 1 5- (4-Methoxy-13-propoxyphenyl) -5-methyl 2-oxazolidinone 0.01

Castor oil 5.0 g

Concentrated glycerin 1.2 g

Polysorbate 80 12.0 g

Sodium chloride 9.0 g

Hydrochloric acid

Sodium hydroxide appropriate amount

Purified water qs

100 mL total volume

pH 7.0

In accordance with the above formula, concentrated glycerin, polysorbate 80 and sodium chloride are added to purified water, and the mixture is dissolved with stirring with a homomixer. The compound dissolved in castor oil is added dropwise and emulsified with a homomixer. Micronize with a microfluidizer. Then adjust the pH and sterilize by filtration to produce eye drops. Example 24 Emulsion ophthalmic solution

(R)-(-) — 5— (4-Methoxy-1-3-propoxyphenyl) 5-Methyl 2-oxazolidinone 0.01 g

Castor oil 1.0 g 2.2 g concentrated glycerin

Polyvinyl alcohol 2.0 g

Hydrochloric acid

Sodium hydroxide appropriate amount

Purified water qs

Total volume 1 00 niL

pH 7.0

According to the above formula, concentrated glycerin and polyvinyl alcohol are added to purified water and dissolved with stirring using a wood mixer. The compound dissolved in castor oil is added dropwise and emulsified with a homomixer. Micronization is performed with a microfluidizer. Then adjust the pH and sterilize by filtration to produce eye drops. Example 2 5 Emulsion ophthalmic solution

(R) 1 (1) 1 5— (4—Methoxyl 3-propoxyphenyl) — 5-Methyl 2-oxoxolidinone 0.01 g

Miglyol 8 1 2 N (medium chain fatty acid triglyceride) 1.0 g

2.2 g concentrated glycerin

Polyvinyl alcohol 2.0 g

Hydrochloric acid

Sodium hydroxide appropriate amount

Purified water qs

Total volume 100 mL

pH 7.0

According to the above formula, concentrated glycerin and polyvinyl alcohol are added to purified water, dissolved with stirring using a wood mixer, and the compound dissolved in Miglyol 812N is added dropwise and emulsified with a homomixer. Micronization is performed with a microfluidizer. Then adjust the pH and sterilize by filtration to produce eye drops. Industrial applicability

The composition for topical administration to the eye of the present invention may be, for example, an ophthalmic solution, a suspended ophthalmic solution, an emulsion or an ointment, allergic conjunctivitis, allergic eye diseases such as spring catarrh, uveitis, blepharitis, lacrimal canalicular It is advantageously used for the treatment of ophthalmic diseases such as inflammation, panophthalmitis and postoperative endophthalmitis. While several embodiments of the present invention have been described in detail, those skilled in the art will recognize that certain embodiments illustrated and modified in various ways without departing substantially from the novel teachings and advantages of the present invention. It is possible to make changes, so such modifications and changes Furthermore, all of them are included in the spirit and scope of the present invention defined in the following claims.

This application is based on Japanese Patent Application No. 2003-2012, which was filed in Japan, and Japanese Patent Application No. 2004-000-178, the contents of which are incorporated in full herein. ing.

Claims

The scope of the claims

I. 5-(4-Methoxy-3-propoxyphenyl) 1-Methyl-2-oxazolidinone or a pharmacologically acceptable salt thereof, topical ocular administration for the treatment of allergic monocular eye disease Composition.

2. 5- (4-Methoxy-3-propoxyphenyl) -5-methyl-21 A composition for topical administration to the eye for the treatment of ocular inflammation, which comprises one-year-old xazolidinone or a pharmacologically acceptable salt thereof.

3.5- (4-Methoxy-1-propoxyphenyl) —5-methyl-21 Composition containing topical xazolidinone or a pharmaceutically acceptable salt thereof for topical ocular administration for the treatment of corneal ulcers object.

4. (R) — (-)-5- (4-Methoxy-3-propoxyphenyl) -1-methyl-2-year-old treatment of allergic eye disease containing xazolidinone or a pharmaceutically acceptable salt thereof For topical administration to the eye.

5. (R)-(-)-5- (4-Methoxy-13-propoxyphenyl) -5-methyl-2-year-old containing xazolidinone or a pharmaceutically acceptable salt thereof for treating ocular inflammation A composition for topical administration to the eye.

6. (R) I (-)-5- (4-Methoxy-3-propoxyphenyl) -5-Methyl-2-year-old containing oxazolidinone or a pharmacologically acceptable salt thereof. For topical administration to the eye.

7. The composition for topical ocular administration according to any one of claims 1 to 6, which is in the form of an aqueous solution.

8. The composition for topical ocular administration according to any one of claims 1 to 6, which is in the form of a suspension.

9. The composition for topical administration to the eye according to any one of claims 1 to 6, which is in the form of an oily ophthalmic solution.

10. The composition for topical ocular administration according to any one of claims 1 to 6, which is in the form of an emulsion.

II. (R)-(-)-15- (4-Methoxy-3-propoxyphenyl) -5-Methyl-2-year-old xazolidinone and its pharmacologically acceptable salt concentration are below the lower limit of 0. The composition for topical ocular administration according to any one of claims 1 to 10, wherein the composition is in a range defined by 0.001 w / v% and an upper limit concentration of 2.0 w_ / v%.

1 2. The composition for ocular topical administration according to any one of claims 1 to 6, which is in the form of an ophthalmic ointment.

1 3. (R)-(-)-5- (4-Methoxy-3-propoxyphenyl) -1-5-Methyl-2-year-old xazolidinone and its pharmacologically acceptable salts The topical ophthalmic solution according to any one of claims 1 to 6 and 12, wherein the concentration is within a range defined by a lower limit concentration of 0.001 wZw% and an upper limit concentration of 10.0 w / w%. Composition.

14.5- (4-Methoxy-1-3-propoxyphenyl) -1-5-methyl-2-one-year aqueous solution containing xazolidinone or a pharmaceutically acceptable salt thereof and hydroxypropyl-1-cyclodextrin .

15. The aqueous liquid preparation according to claim 14, wherein the concentration of hydroxypropyl mono-jS-cyclodextrin has a lower limit of 0.5 wZv% and an upper limit of 25 w / v%.

16.5- (4-Methoxy-3-propoxyphenyl) -1-5-methyl-2 year old xazolidinone and its pharmacologically acceptable salt concentration are lower limit concentration 0.001 wZV% and upper limit concentration 16. The aqueous liquid preparation according to claim 14 or 15, which is in a range specified by 2.0 w / V%.

17. The aqueous liquid preparation according to any one of claims 14 to 16, wherein the pH of the aqueous liquid preparation is in the range of 3 to 9.

18. The aqueous solution according to any one of claims 14 to 17, which is an ophthalmic solution.

1 9. The aqueous solution according to any one of claims 14 to 17, which is a nasal drop.

20. The aqueous solution according to any one of claims 14 to 17, which is an eardrop.

2 1. (R)-(-) — 5— (4-Methoxy-3-propoxyphenyl) — 5-Methyl-2-year-old xazolidinone or its pharmacologically acceptable salt 0.0 1 \ ^ Aqueous ophthalmic solution containing 0.1 to 0.1 w / v% and hydroxypropyl mono-) 8-cyclodextrin 3.0 w / v% to 12.5 wZv%.

22.5- (4-Methoxy-3-propoxyphenyl) -1-5-methyl-2-oxazolidinone or a pharmacologically acceptable salt thereof with hydroxypropyl-1 ^ -cyclodextrin. A method for solubilizing and stabilizing 5- (4-methoxy-13-propoxyphenyl) -1-5-methyl-2-year-old xazolidinone and its pharmaceutically acceptable salt in an aqueous solution .

2 3. (R) I (I) I 5- (4-Methoxy-13-propoxyphenyl) I 5-Methyl-2 One year old xazolidinone or a pharmaceutically acceptable salt thereof in an oily liquid base. An oily liquid composition for topical administration, wherein the base comprises castor oil and Z or a medium chain fatty acid triglyceride.

24. (R) I (I) I 5- (4-Methoxy-13-propoxyphenyl)-5-Methyl-2-year-old xazolidinone and its pharmacologically acceptable salts 24. The oily liquid composition for topical administration according to the above item 23, wherein the concentration is within a range defined by a lower limit concentration of 0.001 wZv% and an upper limit concentration of 2.0 w / v%.

28. Prevent racemization of (R)-(1-)-5- (4-methoxy-13-propoxyphenyl) -15-methyl-2-one-year-old xazolidinone and its or a pharmaceutically acceptable salt thereof in liquid form (R) — (—) — 5 _ (4 — methoxy-13-propoxyphenyl) — 5-methyl-12-oxazolidinone and / or a pharmacologically acceptable salt thereof. A method comprising blending an oil and / or a medium-chain fatty acid triglyceride into an oily liquid preparation.